Inactivation of genes for controlling cell growth in organisms is a tumorigenesis marker. Epigenetic mechanisms causing gene inactivation mainly include DNA methylation, histone acetylation and modifications of other ingredients in higher-order chromatin structures. These modifications change chromatin configurations to cause achange of gene transcription regulation. Genetic transcription disorders may cause abnormal cell proliferation, thereby causing tumors.
More than 40 years ago, Allfrey et al. has recognized that the histone acetylation process is closely related to eukaryotic gene transcriptional regulation (Allfrey V G, Faulkner R, Mirsky A E. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis [J]. Proc Natl Acad Sci USA, 1964, 51: 786-794). The historic acetylation plays a key role in transcriptional regulation of eukaryocytes. The acetylation modification of histone occurs on an epsilon-amino of N-terminal evolutionarily conserved lysine residues and the modification on H3 and H4 is more universal than that on H2A and H2B. Relatively important acetylation loci refer to Lys9 and Lys14 on H3 and Lys5, Lys8, Lys12 and Lys16 on H4. Through acetylation of HAT, aminos of N-terminal lysine of histone are acetylated, positive charges on the aminos are eliminated, negative charges on DNA molecules contribute to spreading DNA conformation, nucleosome structures are relaxed, transcription factors and collaborative transcription activators are facilitated to contact with the DNA molecules, and the histone acetylation can activate specific gene transcriptional expression. Conversely, the histone acetylation is not favorable for expressions of specific genes (such as Rb, p21 and p27). The acetylation and deacetylation of the histone become selector switches of the expressions of the specific genes (Thiagalingam S, Cheng K H, Lee H J, et al. Histonedeacetylases: unique players in shaping the epigenetic histone code [J]. Ann N Y Acad. Sci, 2003, 983; 84-100).
The histone acetylation is regulated by a pair of proteases with mutually antagonistic functions, that is, histone acetyltransferases (HATs) and histone deacetylases (HDACs). The pair of proteases is in a dynamic balance state in normal cells. Generally, histone acetylation level enhancement is related to gene transcription viability enhancement, while too low acetylation level is related to gene expression inhibition (Forsberg E C, Bresnick E H. Histone acetylation beyond promoters: long-range acetylation patterns in the chromatin world[J]. Bioessays, 2001, 23(9): 820-830). Research finds that the HDAC is overexpressed and recruited by a transcription factor to cause abnormal inhibition of the specific genes, thereby causing tumors and other diseases; however, the HDAC viability inhibition may cause growth inhibition and apoptosis of many cancer cells (Somech R, Izraeli S, J Simon A. Histone deacetylase inhibitors-a new tool to treat cancer [J]. Cancer Treat Rev, 2004, 30(5): 461-472). Therefore, the HDAC has become a latest and most popular target in the existing anti-tumor drug research and development field.
An HDAC inhibitor can inhibit HDAC enzyme viability, and an action mechanism of the inhibitor is to block inhibited gene expression caused by HDAC recruiting dysfunctions by inhibiting the HDAC and to change a chromatin structure by changing the degree of acetylation of the histone, thereby regulating the gene expression to treat cancers. The inhibitor has obvious curative effects for treating hematopoietic tumors and solid tumors by inducing growth arrest, differentiation or apoptosis of tumor cells. The HDAC inhibitor has tumor specificity and has a cytotoxic effect to proliferative and dormant aberrant cells, while normal cells have more than 10 times of tolerance to the HDAC inhibitor, and growth arrest and apoptosis of the normal cells may not be caused. Moreover, the clinical dosage of the HDAC inhibitor is far lower than the maximum human tolerance, and the inhibitor has low toxicity to the organisms. The development and utilization of the HDAC inhibitor has become a new hot spot of tumor therapy.
At present, the HDAC inhibitors which have been researched and developed can he classified into five categories: (1) hydroxamic acid compounds with a functional group of hydroximic acid, including representatives such as TSA, SAHA (Curtin M L, Garland R B, Heyman H R, et al. Succinimide hydroxamic acids as potent inhibitors of histone deacetylase[J]. Bioorg Med Chem Lett, 2002, 12(20) 2919-2923), LAQ824 (Atadja P, Hsu M, Kwon P, et al. Moleculer and cellular basis for the anti-proliferative effects of the HDAC inhibitor LAQ824. Novartis Found Symp, 2004, 259: 249-266); (2) cyclic tetrapeptides containing 2-amino-8-oxo-9,10-epoxy capryl or not containing the group, such as FK-228; (3) benzamide compounds, wherein a representative MS-275 has been clinically studied; (4) short-chain fatty acids, such as butyric acid and phenylbutyric acid; and (5) others; the HDAC inhibitors do not have structural characteristics of general HDAC, but contain some or all structural subunits required for inhibiting the HDAC viability.
For example, a Chinese patent CN 103420917 A discloses a benzamide compound containing a condensed ring structure shown as a formula A, and histone deacetylase inhibitory viability and applications in treating malignant tumors and differentiation and proliferation related diseases. A Chinese patent CN 103288728 A discloses a naphthoamide derivative shown as a formul B, and the naphthoamide derivative can effectively treat some diseases caused by protein kinase regulation abnormality. A Chinese patent CN 103539695 A discloses a substituted diphenyl ether histone deacetylase inhibitor shown as a formula C. A Chinese patent CN 103467359 A discloses an indole-containing cinnamamide histone deacetylase inhibitor shown as a formula D. A Chinese patent. CN 102659630 A discloses a hydroxamic acid compound shown as a formula E.

A Chinese patent CN 102786458 A discloses a pyrrole formamide derivative shown as a formula F, application as an anti-malignant tumor drug, and particularly an application in preparing medicines for treating breast cancer, lung cancer and gastric cancer.

R1, R2, R3 and R4 are: C1-C6 linear alkyl or branched alkyl, C3-C6 naphthenic base;
R5 and R6 are simultaneously or respectively: hydrogen C1-C6 alkyl; hydroxyl, halogen, C1-C4 alkoxy, nitrate-substituted C1-C6 alkyl.
At present, SAHA developed by Merck company is a listed histone deacetylase inhibitor, is only limited to treatment of skin T cell lymphoma and does not have obvious curative effects on many other cancers. Other developed HDAC inhibitors have certain problems in antitumor viability, toxic and side effects, subtype selectivity and the like. Therefore, development of a novel compound with the histone deacetylase inhibitory viability has very important social and economic significances.